|Publication number||US7855082 B1|
|Application number||US 12/350,665|
|Publication date||Dec 21, 2010|
|Filing date||Jan 8, 2009|
|Priority date||Oct 31, 2001|
|Publication number||12350665, 350665, US 7855082 B1, US 7855082B1, US-B1-7855082, US7855082 B1, US7855082B1|
|Original Assignee||Astrazeneca Ab|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (35), Non-Patent Citations (3), Classifications (6), Legal Events (3)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application is a continuation of U.S. patent application Ser. No. 11/284,434, filed 21 Nov. 2005 now abandoned, which is a continuation of U.S. patent application Ser. No. 10/284,828, filed 31 Oct. 2002, abandoned, which claims the benefit of provisional U.S. Patent Application Ser. No. 60/334,853, filed 31 Oct. 2001.
The present invention relates to a novel method to determine the ratio of 5-methoxy and 6-methoxy isomers of omeprazole present in a mixture thereof. The method uses different Raman scattering efficiency values for the 5-methoxy and 6-methoxy isomers.
Omeprazole is a proton pump inhibitor, i.e. effective in inhibiting gastric acid secretion, and is useful as an antiulcer agent In a more general sense, omeprazole may be used for treatment of gastric-acid related diseases in mammals and especially in man.
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, having the generic name omeprazole, as well as therapeutically acceptable is salts thereof, are described in EP 5129. Ohishi et al., Acta Cryst (1989), C45, 1921-1923, describe single crystal X-ray data and the derived molecular structure of one crystal form of omeprazole. A second crystal form of omeprazole is disclosed in WO 99/08500. These crystal forms are referred to herein as omeprazole forms B and A, respectively.
WO 01/14367 discloses isomers of omeprazole having the methoxy group on the benzimidazole ring at either the 6- or the 5-position. These two forms are referred to herein as “6-methoxy” and “5-methoxy”, respectively or alternatively referred to as “6-isomer” and “5-isomer”, respectively. WO 01/13919 discloses a method based on FT-Raman spectroscopy to determine the ratio of the 6- and 5-isomer of omeprazole present in a mixture thereof. The method of WO 01/13919 is based on the assumption that the 5-isomer and the 6-isomer have the same Raman scattering efficiency.
Isomers are chemical compounds that have the same molecular formulae but different molecular structures or different arrangements of atoms in space (see A Dictionary of Science, Oxford University Press, 1999). In structural isomerism the molecules have different molecular structures, i.e. they may be different types of compound or they may simply differ in the position of the functional groups in the molecule. Structural isomers generally have different physical and chemical properties. Tautomerism is a type of isomerism in which the two isomers (tautomers) are in equilibrium. The most wellknown tautomerism is the keto-enol tautomerism. In the keto-enol tautomerism one compound containing a —CH2—CO— group (the keto form of the molecule) is in equilibrium with one containing the —CH═C(OH)— group (the enol). The keto-enol tautomerism occurs by migration of a hydrogen atom between a carbon atom and the oxygen on an adjacent carbon. Tautomers can therefore be said to be isomers that are rapidly interconverted in solution phase. The keto-enol tautomerism is schematically shown in Scheme 1 below.
Benzimidazole is also wellknown to exhibit tautomerism, see e.g. Lee and Jeoung, “Synthesis and Tautomerism of 2-Aryl- and 2-heteroaryl Derivatives of Benzimidazole”, J. Heterocyclic Chem., 33, 1711 (1996); and Jacoby et al, “A comparison of intermolecular vibrations and tautomerism in benzimidazole, benzotriazole and their binary water clusters”, Appl. Phys. B71, 643-639, (2000), and its 13C-NMR spectrum shows only four peaks in spite of seven carbon atoms being present. Structure, atom numbering, and tautomerism of benzimidazole are shown in Scheme 2 below.
In the benzimidazole case the tautomerism occurs by migration of a hydrogen atom between the two nitrogen atoms. However, the 1H and “3H” tautomers are identical to each other unless the benzimidazole is assymetrically substituted. This phenomenon is discussed in U.S. Pat. No. 5,039,806 which relates to 2-pyridinyl methylsulfinyl benzimidazole compounds structurally related to omeprazole.
Omeprazole with its methoxy group in the 5 position of the benzimidazole is monosubstituted and is thus assymetrically substituted. Consequently the 1H and “3H” tautomers are not identical. The IUPAC-nomenclature of these two isomers are 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, referred to herein as the 5-methoxy and 6-metoxy isomers, as is indicated in Scheme 3 above.
The 5-isomer of omeprazole is thus a tautomer to the 6-isomer of omeprazole.
As discussed above tautomers are isomers that are rapidly interconverted in solution. This interconversion is very rapid but can be slowed down by decreasing the temperature. Two tautomers usually have different energy in solution and one tautomer (or isomer) is therefore of lower energy and more stable.
Solid phase is different from solution phase and the interconversion of tautomers (isomers) is usually non-existing in the solid phase. However, two tautomers may still be of different energy and one tautomer may therefore be more stable than the other also in the solid state.
Crystallisation is a process to precipitate a solid material from a solution thereof by allowing the concentration of the material to be above the saturation point so that the excess of the material is separated as crystals.
Polymorphism is the ability of elements or compounds to exist in more than one crystal is form, with each having the same chemical composition but different physical properties due to differences in the arrangement of atoms (A Dictionary of Earth Sciences, Oxford University Press 1999). Examples of polymorphs are graphite and diamond (both carbon); alpha and beta quartz (both SiO2); and calcite (hexagonal) and aragonite (orthorhombic), both forms of CaCO3. The external form of the crystal is referred to as the crystal habit. The atoms, ions, or molecules forming the crystal have a regular arrangement and this is the crystal structure (A Dictionary of Science, Oxford University Press, 1999).
Polymorphs differ in their crystal structures and they often have different properties, like rate of dissolution, stability and melting point. Different polymorphs can be characterized by e.g. X-ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC), microscopy or spectroscopy. XRPD measurements show mainly variation in the unit cell parameters, while Raman spectroscopy mainly shows differences in molecular conformation. It is common in polymorphs that both the unit cell and the molecular conformation vary.
Omeprazole exists in two different crystal forms (polymorphs). The first is disclosed by Ohishi et al., Acta Cryst (1989), C45, 1921-1923, and is referred to as omeprazole form B. The second polymorph is disclosed in WO 99/08500 and is referred to as omeprazole form A. Omeprazole form A is in the solid state more stable than omeprazole form B, both thermodynamically and chemically. Omeprazole form B can be converted into form A by recrystallisation.
Omeprazole form A consists of the 6-isomer and omeprazole form B consists of a mixture of the 6- and 5-isomers, more specifically it consists of about 86% 6-isomer and about 14% 5-isomer (corrected values).
The different isomers and crystal forms of omeprazole can thus either be explained as a difference in the distribution of 5- and 6-methoxy isomer, or as a difference in the distribution between crystal forms A and B.
The amount of form A and form B is related to the amount of 5-isomer and 6-isomer, pure form A having no 5-isomer, pure form B having about 20% 5-isomer, and about 80% 6-isomer (FT-Raman values, not corrected for solid-state NMR data). The corresponding corrected values for form B is as discussed above about 86% 6-isomer and about 14% 5-isomer.
In the Raman spectrum of omeprazole, a peak is observed at 1355 cm−1. If the 5-methoxy isomer is present, an additional Raman peak is observed at 1364 cm−1 that is absent for the spectrum of pure 6-methoxy isomer. If the intensity of the two peaks is measured then the relative amount of 5- and 6-methoxy isomer present in a mixture thereof can be determined from the peak ratio.
However, it has now surprisingly been found that the two isomers of omeprazole have different Raman scattering efficiency and this has to be taken into account when calculating the amount of 5- and 6-isomer of omeprazole. If this is not properly done the wrong ratio of 5- and 6-isomer of omeprazole present in a mixture thereof will be calculated. This is of importance since mixtures, wherein the isomers have different ratios, have different solid state stability.
The FT-Raman spectrum is specific for omeprazole and differs from that of even closely related compounds, eg omeprazole salts. The band pair at 1355/1364 cm−1 is characteristic for the 5- and 6-isomers of omeprazole.
It has surprisingly been found that the two isomers of omeprazole have different Raman scattering efficiency. It is thus an object of the present invention to provide a method determine the ratio of 5-methoxy and 6-methoxy isomers of omeprazole using different Raman scattering efficiency values for the 5-methoxy and 6-methoxy isomers. The present method using scaled Raman scattering efficiency values is advantageous since it gives the true amount of the 5-isomer and 6-isomer of omeprazole present in a mixture thereof.
Omeprazole form A is thermodynamically more stable than form B. It has additionally surprisingly been found that the amount of omeprazole form A present in a mixture of omeprazole form A and B is of importance for the stability of said mixture. The higher amount of omeprazole form A present in a mixture the more stable the mixture tends to be.
It is therefore of great importance to be able to adequately determine the ratio of 5-methoxy and 6-methoxy isomers of omeprazole in a mixture thereof.
The amount of 5- and 6-isomer was determined with FT-Raman spectroscopy and with solid-state NMR spectroscopy (ssNMR), and a correlation was calculated between the two methods, using linear regression. In the FT-Raman determination there is one unknown, since it is assumed that the 5-isomer and the 6-isomer have the same Raman scattering efficiency. With this assumption, the following data were obtained, as reported in Table 1.
Determination of fraction of 5-isomer with
FT-Raman and ssNMR analysis.
The data are also illustrated in
Table 1 and
This leads to the following numbers:
−0.0062 × 0.64 = −0.0040
1.5655 × 0.64 = 1.00
The relative amount of 5-isomer is determined by Raman spectroscopy from the following equation: Amount of 5-isomer=I1364(I1355+I1364)×0.64.
Thus, the 5-isomer has a higher Raman scattering efficiency than the 6-isomer.
For NMR spectroscopy, the signal from a carbon atom in a certain position is directly proportional to the concentration. Hence, no scattering efficiency is involved and no correction is necessary for ssNMR. Moreover, because of the closeness of the 1355 and 1364 cm−1 Raman bands, the relative Raman scattering efficiency determined will be independent of the Raman instrument used.
XRPD can also be used to determine the relative amounts of 5- and 6-isomer in a mixture thereof. XRPD data confirms that the scaling factor between uncorrected and corrected values is 0.64.
Tests have been performed on omeprazole form A, form B and mixtures thereof with XRPD and FT-Raman spectroscopy. The XRPD measurements on the A and B forms indicate differences in the unit cell dimensions (
As a comparison, testing has been done on batches 100, 101 and 102.
TABLE 2 The batches shown in the figures and the 5/6-isomer ratio determined by FT-Raman spectroscopy and the A/B ratio determined with XRPD. % 5-isomer % 5-isomer (uncorrected values) Ratio A/B-form (corrected values) Batch [Raman spectroscopy] [XRPD] [Raman spectroscopy] Form A <2% 100:0 <2% 100 2 99:1 <2% 101 12 54:46 8% 102 18 22:78 12 % Form B 20 0:100 14 %
Solid State NMR
The ratio of 5-methoxy and 6-methoxy isomers of omeprazole present in a mixture thereof can also be determined by Solid State NMR (ssNMR), e.g. using cross polarization magic angle spinning (CP-MAS) technique.
In order to arrive at a complete assignment, a specifically 13C-labelled sample was synthesized which gives a hundred-fold NMR-intensity increase for the seven enriched carbon atoms of the benzimidazole group. The spectrum for 13C-labelled omeprazole was assigned with a 2D RFDR experiment and clearly shows two similar but separate correlation networks attributed to the 5- and 6-methoxy isomers. The chemical shift differences caused by the tautomerism are of similar magnitude as those obtained from solution NMR experiments. The combined data result in unambigous assignments for every carbon atom of omeprazole, though there are some overlapping signals. Spectral regions containing non-overlapping signals from the 5- and 6-methoxy isomers can be used for quantification also for natural abundance omeprazole samples.
The ratio of 5-methoxy and 6-methoxy isomers of omeprazole present in a mixture thereof can also be determined by X-ray powder diffraction.
The FT-Raman spectrum is specific for omeprazole and differs from that of even closely related compounds, eg omeprazole salts. The band pair at 1355/1364 cm−1 thus characteristic for the 5- and 6-isomers.
Repeatability of Analysis
Repeatability was done for batch ASP 255. Three operators analyzed the batch and evaluated the data. For every spectrum, a new sampling was made from the same jar. The results are reported in Table 3, where average, standard deviation, and relative standard is deviation are shown. Thus, repeatability was found to be high. The data in Table 3 are reported without correction factor.
TABLE 3 Determination of fraction of 5- and 6-isomer with FT-Raman spectroscopy, for omeprazole batch ASP 255 (without correction factor). I1364/ I1364/ I1364/ (I1355 + I1364) (I1355 + I1364) (I1355 + I1364) Operator 1a) Operator 2 Operator 3 1 0.115 (0.112) 0.112 0.112 2 0.118 (0.114) 0.112 0.115 3 0.115 (0.112) 0.112 0.115 4 0.118 (0.113) 0.112 0.115 5 0.118 (0.113) 0.112 0.115 6 0.118(0.114) 0.110 0.115 7 0.115 8 0.115 9 0.115 10 0.112 N 6 6 10 Average 0.117 0.112 0.114 Standard deviation 0.0015 0.0008 0.0013 Relative S. Dev. 1.3% 0.7% 1.1% a)Values in parenthesis determined with computer software.
Intermediate precision can be evaluated from the averages in Table 3. Moreover, intermediate precision was determined from measurement on 10 different batches which were analyzed on the same instrument, by the three different operators, on different days, with new sampling for every spectrum. These measurements are reported in Table 4.
Determination of fraction of 5- and 6-isomer with FT-Raman
spectroscopy, for 10 batches of omeprazole (n = 1).
The 10 batches gave average values in the range 0.019-0.447, with standard deviation in the range 0.001-0.005. Relative standard deviation was in the range 0.9-8.8%, naturally with higher RSD for low fraction of 5-isomer.
For all the measurements reported in Tables 3-4, I1364 and I1355 were evaluated graphically to from printed figures. For measurements number 1-6 by operator 1 in Table 3, computer software was used to determine I1364 and I1355, with subtraction of the baseline around 1328 cm−1, I1328. Whereas the graphical evaluation in Table 3 gave values of 0.115-0.118, the computer evaluation gave values of 0.112-0.114. This deviation is similar to the difference between different operators using graphical evaluation (see Table 3).
In Table 4, the sample with 1.9% 5-isomer was determined by the three operators with a standard deviation of 0.1%. Hence, the quantitation limit can be set as 2% 5-isomer, uncorrected value, which corresponds to 1,3% 5-isomer, corrected value.
Detection limit is illustrated in
The present method is seen from Tables 1 and 2 and
The method of the present invention can be used to determine the ratio of 5-methoxy and 6-methoxy isomers of omeprazole present in a mixture thereof in bulk form as well as in admixture with pharmaceutical excipients, e.g. conventional pellets.
An example of instrument and settings is given below:
Perkin-Elmer System 2000 NIR FT-Raman
6.47 mm, corresponding to 4 cm−1
at 15000 cm−1
500 mW at sample
Number of scans:
Place omeprazole substance or powder in a suitable holder, then place the holder in the FT-Raman instrument. Preferably, place the compound in a suitable glass container, eg ca 30 mg of compound in an NMR tube with 5 mm outer diameter, tap the sample to pack it, then place the tube in the FT-Raman instrument in a holder that is able to rotate the sample.
Record the FT-Raman spectrum between 0 and 4000 cm−1.
Also record the FT-Raman spectrum of a reference sample that is pure 6-isomer. Alternatively, retrieve such spectrum from a library.
Display the spectrum obtained together with the spectrum of pure 6-isomer in the region 1380-1320 cm−1, and normalize on the 1355 cm−1 peak (on Perkin-Elmer 2000 use: “autoscale y”). Measure the intensity I1355 at 1355 cm−1, with subtraction of the background around 1328 cm−1. Measure the intensity I1364 at 1364 cm−1, with subtraction of the background obtained from the normalized spectrum of the pure 6-isomer.
The relative amount of 5-isomer is determined by Raman spectroscopy from the following equation:
Amount of 5-isomer=I 1364/(I 1355 +I 1364)×0.64.
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|2||Ohishi et al., Acta Cryst (1989), C45, 1921-1923.|
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|U.S. Classification||436/164, 436/171, 546/273.7|
|Aug 1, 2014||REMI||Maintenance fee reminder mailed|
|Dec 21, 2014||LAPS||Lapse for failure to pay maintenance fees|
|Feb 10, 2015||FP||Expired due to failure to pay maintenance fee|
Effective date: 20141221